The genus Rumex (Polygonaceae): an ethnobotanical, phytochemical and pharmacological review

Rumex L., a genus in Polygonaceae family with about 200 species, is growing widely around the world. Some Rumex species, called "sorrel" or "dock", have been used as food application and treatment of skin diseases and hemostasis after trauma by the local people of its growing areas for centuries. To date, 29 Rumex species have been studied to contain about 268 substances, including anthraquinones, flavonoids, naphthalenes, stilbenes, diterpene alkaloids, terpenes, lignans, and tannins. Crude extract of Rumex spp. and the pure isolates displayed various bioactivities, such as antibacterial, anti-inflammatory, antitumor, antioxidant, cardiovascular protection and antiaging activities. Rumex species have important potential to become a clinical medicinal source in future. This review covers research articles from 1900 to 2022, fetched from SciFinder, Web of Science, ResearchGate, CNKI and Google Scholar, using “Rumex” as a search term ("all fields") with no specific time frame set for the search. Thirty-five Rumex species were selected and summarized on their geographical distribution, edible parts, traditional uses, chemical research and pharmacological properties.

Page 2 of 29 Li et al. Natural Products and Bioprospecting (2022) 12:21 regarded as noxious weeds because oxalic acid makes them difficult to be digested [12]. To date, 268 components from 29 Rumex species have been reported. Anthraquinones, flavonoids, tannins, stilbenes, naphthalenes, diterpene alkaloids, terpenes, and lignans were as the main chemical components, with a broad spectrum of pharmacological activities, such as anti-inflammatory, antioxidant, antibacteria, antitumor, and antidiabetic activities [13][14][15][16][17]. In addition to important role of Rumex in the traditional applications, researchers also regard Rumex as a potential effective medicine of many diseases. This article has reviewed a comprehensive knowledge on the distribution, traditional uses, chemistry and bioactivity progress of Rumex, and their therapeutic applications and utilizations were provided.

Geographical distributions, local names, parts used and traditional uses
The genus Rumex with more than 200 species, is distributed widely in the world and has been used traditionally in many regions, e.g., Asia, America, Europe and other continents. Many of them known as "sorrel" or "dock" have a long history of food application and medicinal uses for the treatment of skin diseases, and hemostasis after trauma by the local people of its growing areas. For example, R. acetosa is commonly used medicinally for diuretics around the world [4]. R. maritimus and R. nepalensis, used as laxatives, have long-term medicinal applications in India as substitutes for Rheum palmatum (Polygonaceae), which is usually used to regulate the whole digestive system. Moreover, Indians have also recorded nine Rumex plants as astringent agents, including R. acetosa, R. acetosella, R. crispus, R. dentatus, R. hastatus, R. maritimus, R. nepalensis, R. scutatus, and R. vesicarius [18]. All seven species included R. acetosa, R. trisetifer, R. patientia, R. crispus, R. japonicus, R. dentatus and R. nepalensis, called "jinbuhuan", have been used for hemostasis remediation in China [19]. R. thyrsiflorus, rich in nutrition, has been used as food by Europeans in history and as folk medicine due to its obvious antiinflammatory activity [20]. R. lunaria has been used to treat diabetes by Canarian medicine [16]. The leaves of more than 14 (Table 1) could be eaten freshly or cooked as vegetables in the folk of many places [5,6]. In Table 1, the geographical distributions, local names, parts used and traditional uses of 35 Rumex species are summarized.
Seco-anthraquinones are oxidized anthraquinones with a loop opened at C-10, resulting in the fixed planar structure of anthraquinone destroyed and causing of a steric hindrance between the two left benzene rings. So far, only two seco-anthraquinone glucosides, nepalensides A (49) and B (50) were reported from the roots of R. nepalensis [33].  [18,19,62,195,197] R7 R. dentatus L       116 Epicatechin- 132

Tannins
Tannins, which may be involved with the hemostasis activity, are abundant in Rumex plants. So far, 25 condensed tannins (114-138) (Fig. 3, Table 2) were reported from the genus Rumex. Chemical investigations on the EtOAc fraction of acetone-water extract of the aerial parts of R. acetosa showed that R. acetosa was rich in tannins.
Rumex polysaccharides have rarely been studied, and only one polysaccharide, RA-P (268), which has a 30 kDa molecular weight and consists of D-glucose and D-arabinose, was reported from R. acetosa [127].

LC-MS analysis
The chemical compositions of Rumex spp. were also analyzed by LC-MS techniques. Untargeted metabolomic profiling via UHPLC-Q-TOF-MS analysis on the flowers and stems of R. tunetanus resulted in the identification of 60 compounds, 18 of which were reported from the Polygonaceae family for the first time. Quercetin-3-O-β-D-glucuronide (73) was found to be the most abundant phenolic compound in flowers and epicatechin-3-Ogallate (110) in stems [103]. Moreover, 44 bioactive components classified as sugars, flavanols, tannins and phenolics were clarified from the flowers and stems of R. algeriensis based on RP-HPLC-DAD-QTOF-MS and MS-MS [102]. The analysis of sex-related differences in phenolics of R. thyrsiflorus has shown female plants of R. thyrsiflorus contain more bioactive components than males, such as phenolic acids and flavonoids, especially catechin (105) [20].

Bioactivity
Rumex has been used as food and medicine in the folk. In addition to important role of Rumex in the traditional application, during the past few decades, it was subjected to scientific investigations of the structure of isolated chemical components and their clinical applications by several research groups. Pharmacological studies on Rumex extracts and its pure components revealed a wide range of bioactivities, involving antimicrobial, antiinflammatory, antiviral, renal and gastrointestinal protective effects, antioxidant, antitumor and anti-diabetes effects.

Anti-inflammatory
The potential effects of anti-inflammatory of AST2017-01 composing of processed R. crispus and Cordyceps militaris which was widely used in folk medicines in Korea, as well as chrysophanol (1) on the treatment of ovalbumin-induced allergic rhinitis (AR) rats were investigated. The serum and tissue nasal mucosa levels of IgE, histamine, TSLP, TNF-α, IL-1, IL-4, IL-5 and IL-13 were both decreased by treatment with AST2017-01 and 1 (positive control: dexamethasone), indicating that R. crispus and 1 has the ability to prevent and treat AR [153]. The aqueous extract of roots of R. patientia has anti-inflammatory action in vivo. The higher dose of extract (150 mg/kg) showed inhibition (41.7%) of edema in rats compared with the positive control, indomethacin (10 mg/kg, 36.6%) [21]. Methanolic extracts of the roots and stems of R. roseus exhibited anti-inflammatory functions in intestinal epithelial cells, reducing TNF-α-induced gene expression of IL-6 and IL-8 [154]. The ethanol extract of the roots of R. japonicus could be a therapeutic agent for atopic dermatitis. Skin inflammation in Balb/c mice was alleviated with the extract in vivo. Moreover, an in vitro experiment showed that the extract of R. japonicus decreased the phosphorylation of MAPK and stimulated NF-κB in TNF-α in HaCaT cells [155]. The methanolic extract of R. japonicus inhibited dextran sulfate sodium (DSS)-induced colitis in C57BL/6 N mice by protecting tight junction connections in the colonic tissue. It was observed that R. japonicus has the potential to treat colitis [156]. Ethyl acetate extract of the roots of R. crispus showed anti-inflammatory activity in inhibiting NO production and decreasing the secretion of proinflammatory cytokines [157].

Antivirus
1,4-Naphthoquinone and naphthalenes from R. aquaticus presented antiviral activity against herpes simplex virus type 2 (HSV-2) replication infected Vero cells. In which, musizin (145) showed dose dependent inhibitory property, causing a 2.00 log 10 reduction in HSV-2 at 6.25 μM, on a traditional virus yield reduction test and qPCR assay. It suggested that R. aquaticus had the potential to treat HSV-2 infected patients [158].

The function in kidney and gastrointestinal tract
It is noted that quercetin-3-O-β-D-glucoside (72, QGC) from R. aquaticus could alleviate the modle that indomethacin (nonsteroidal anti-inflammatory drugs) induced gastric damage of rats and ethanol extract of R. aquaticus had a protective effect on the inflammation of gastric epithelial cells caused by Helicobacter pylori. In vivo research suggested that QGC pretreatment could decrease gastric damage by increasing mucus secretion, downregulating the expression of intercellular adhesion molecule-1 and decreasing the activity of myeloperoxidase. The in vitro test found that flavonoids including QGC could inhibit proinflammatory cytokine expression and inhibit the proliferation of an adenocarcinoma gastric cell line (AGS) [159,160]. The cytoprotective effect of QGC against hydrogen peroxide-induced oxidative stress was noticed in AGS [161]. Moreover, QGC also showed protective efficiency in a rat reflux esophagitis model in a dose-dependent manner (1-30 mg/kg) [162].

Antioxidant properties
An extraction technology to obtain the total phenolics of R. acetosa was optimized and the antioxidant activity of different plant parts of R. acetosa was well investigated. It was found that the 80% methanol extract of the roots (IC 50 = 118.8 μM) showed higher scavenging activity to DPPH free radicals than the other parts (leaves: IC 50 = 201.6 μM, flowers and fruits: IC 50 = 230.1 μM, stems: IC 50 = 411.2 μM) [163]. The roots of R. thyrsiflorus [164], ethanol extracts of R. obtusifolius and R. crispus showed antioxidant ability on DPPH, ABTS + and FRAP assays [165]. Moreover, R. tingitanus leaves, R. dentatus, R. rothschildianus leaves, R. roseus and R. vesicarius also showed antioxidant activity on DPPH assay [13,78,105,154,166,167]. Phenolics isolated from R. tunetanus flowers and stems displayed antioxidant properties on DPPH and FRAP assays [103]. DPPH, ABTS + , NO 2 − radical scavenging and phosphomolybdate antioxidant assays verified that R. acetosella has antioxidant properties [168]. Phenolic constitutions from R. maderensis dispalyed antioxidant activity after the gastrointestinal digestion process. These components are known as dietary Page 23 of 29 Li et al. Natural Products and Bioprospecting (2022) 12:21 polyphenols and have the potential to be developed as functional products [99]. Moreover, the total antioxidant capacities of R. crispus were found to be 49.4%-86.4% on DPPH, ABTS + , NO, phosphomolybdate and SPF assays, which provided the basis to develop R. crispus as antioxidant, antiaging and skin care products [169]. Later on, the ripe fruits of R. crispus were studied and the aqueous extract showed antioxidant activity in vitro [170]. Dichloromethane and ethyl acetate extracts of R. crispus exhibited stronger antioxidant activity, which were associated with the concentration of polyphenols and flavonoids [157]. The antioxidant activities of chrysophanol (1), 1,3,7-trihydroxy-6-methylanthraquinone (54), przewalskinone B (55) and p-coumaric acid (206) isolated from R. hastatus were investigated on a nitric oxide radical scavenging assay, whose IC 50 values were 0.39, 0.47, 0.45, and 0.45 mM, respectively [134].

Antitumor properties
MTT assays on HeLa (human cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (human breast adenocarcinoma) cell lines showed that R. acetosa and R. thyrsiflorus could inhibit the tumor cell proliferation [171]. The fruit of R. crispus showed cytotoxicity on HeLa, MCF7 and HT-29 (colon adenocarcinoma) cells in vitro [170]. The methanolic extract of R. vesicarius was assessed for hepatoprotective effects in vitro. CCl 4 -induced hepatotoxicity was observed at 100 mg/ kg bw and 200 mg/kg bw. The plant also has cytotoxicity in HepG2 (human hepatoma cancer) cell lines [172]. Dichloromethane extract of R. crispus roots inhibited the growth and induced cellular apoptosis of HepG2 cells [157]. The hexane fraction of R. rothschildianus leaves showed 98.9% and 97.4% inhibition of HeLa cells and MCF7 cells at a concentration of 4 mg/mL [105].
Different plant parts (stems, roots, flowers and leaves) of R. vesicarius were screened for their cytotoxicity by the MTS method on MCF7, Lovo and Caco-2 (human colon cancer), and HepG2 cell lines. The stems displayed stronger cytotoxicity in vitro and with nontoxicity on zebrafish development, with IC 50 values of 33.45-62.56 μM. At a concentration of 30 µg/mL, the chloroform extract of the stems inhibited the formation of ≥ 70% of intersegmental blood vessels and 100% of subintestinal vein blood vessels when treated zebrafish embryos, indicating the chloroform extract of R. vesicarius stems has apparent antitumor potential [15].
2-Methoxystypandrone (152) from R. japonicus exhibited antiproliferative effect on Jurkat cells and the potential to treat leukemia, by reducing the mitochondrial membrane potential and increasing the accumulation of mitochondrial reactive oxygen, as shown by flow cytometry [116]. The phenolic extract from the flower parts of R. acetosa exhibited in vitro antiproliferative effects on HaCaT cells. When increasing of the extract concentration from 25 μg/mL to 100 μg/mL, the proliferation ability on HaCaT cells gradually decreased [147].
The hypoglycemic effects of oral administration of ethanol extract of R. obtusifolius seeds (treatment group) were compared to the control group (rabbits with hyperglycemia). The treatment group could decrease fasting glucose levels (57.3%, p < 0.05), improve glucose tolerance and increase the content of liver glycogen (1.5-fold, p < 0.01). It also not only reduced the total cholesterol, low-density lipoprotein cholesterol levels and liver enzyme levels, but increased the high-density lipoprotein cholesterol levels. The results showed that R. obtusifolius has great potential to treat diabetes [173]. In addition, phenolic components of R. dentatus showed the ability to ameliorate hyperglycemia by modulating carbohydrate metabolism in the liver and oxidative stress levels and upregulating PPARγ in diabetic rats [14].
The antiplatelet activity of R. acetosa and the protective mechanism on cardiovascular system were investigated yet. The extract of R. acetosa showed inhibition of the collagen-induced platelet aggregation by modulating the phosphorylation of MAPK, PI3K/Akt, and Src family kinases and inhibited the ATP release in a dose dependent manner (25-200 μg/mL) [176]. The absorption of fexofenadine was inhibited by the ethanol extract of R. acetosa to decrease the aqueous solubility of fexofenadine [177]. The hepatoprotective effect of R. tingitanus was investigated by an in vivo experiment, in which the ethanol extract protected effectively the CCl 4 -damaged rats by enhancing the activity of liver antioxidant enzymes. Moreover, the extract could reduce the immobility time of mice, comparable of the positive drug, clomipramine. The results indicated that R. tingitanus has antidepressant-like effects [78].
The anti-Alzheimer effect of helminthosporin (51) from R. abyssinicus was investigated in PAMPA-BBB permeability research, showing that 51 inhibited obviously AChE and BChE with IC 50 values < 3 μM. Compound 51 could not only cross the BBB with high BBB permeability, but also bind with the peripheral anion part of the cholinesterase activity site by molecular docking [80].
Inhibition of human pancreatic lipase could reduce the hydrolysis of triacylglycerol into monoacylglycerol and free fatty acids [181]. Chrysophanol (1) and physcion (18) from R. nepalensis with good inhibitory activity on pancreatic lipase (Pearson's r = 0.801 and 0.755, respectively) showed the obvious potential to treat obesity [182].

Conclusion
The genus Rumex distributing widely in the world with more than 200 species has a long history of food and medicinal application in the folk. These plants with rich secondary metabolites, e.g., quinones, flavonoids, tannins, stilbenes, naphthalenes, terpenes, diterpene alkaloids, lignans and other type of components, showed various pharmacological activities, such as antimicrobial, anti-inflammatory, antiviral, renal and gastrointestinal protective effects, antioxidant, antitumor and anti-diabetes effects. Particularly, quinones as the major components in Rumex showed stronger antibacterial activities and exerted the potential to treat kidney disease. However, detailed phytochemical studies are needed for many Rumex species, in order to clarify their bioactive components. Further studies and application may focus on the antitumor, anti-diabetes, anti-microbial, hepatoprotective, cardiovascular and gastrointestinal protective effects. Moreover, the toxicity or side effects for Rumex plants and their chemical constituents should be evaluated, in order to make the uses of Rumex more safety.